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Phase II trial of pegylated liposomal doxorubicin plus docetaxel with and without trastuzumab in metastatic breast cancer: Eastern Cooperative Oncology Group Trial E3198

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Abstract

The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)–docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m2) and docetaxel (60 mg/m2) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in ~10% of patients. In conclusion, concurrent administration of trastuzumab with PLD–docetaxel was not associated with higher risk of cardiac toxicity compared with PLD–docetaxel alone, but led to excessive hand-foot syndrome.

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References

  1. A’Hern RP, Smith IE, Ebbs SR (1993) Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67:801–805

    PubMed  Google Scholar 

  2. Nabholtz JM, Gelmon K, Bontenbal M et al (1996) Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858–1867

    CAS  PubMed  Google Scholar 

  3. Ravdin PM, Burris HA III, Cook G et al (1995) Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13:2879–2885

    CAS  PubMed  Google Scholar 

  4. Aapro M (1998) Docetaxel versus doxorubicin in patients with metastatic breast cancer who have failed alkylating chemotherapy: a preliminary report of the randomized phase III trial. 303 Study Group. Semin Oncol 25:7–11

    CAS  PubMed  Google Scholar 

  5. Sledge GW, Neuberg D, Bernardo P et al (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21:588–592

    Article  PubMed  Google Scholar 

  6. Ghersi D, Wilcken N, Simes J et al (2005) Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev CD003366

  7. Sparano JA (1999) Doxorubicin/taxane combinations: cardiac toxicity and pharmacokinetics. Semin Oncol 26:14–19

    CAS  PubMed  Google Scholar 

  8. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  CAS  PubMed  Google Scholar 

  9. Bangham AD, Horne RW (1964) Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. J Mol Biol 8:660–668

    Article  CAS  PubMed  Google Scholar 

  10. Berry G, Billingham M, Alderman E et al (1998) The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 9:711–716

    Article  CAS  PubMed  Google Scholar 

  11. Safra T, Muggia F, Jeffers S et al (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11:1029–1033

    Article  CAS  PubMed  Google Scholar 

  12. Vaage J, Mayhew E, Lasic D et al (1992) Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes. Int J Cancer 51:942–948

    Article  CAS  PubMed  Google Scholar 

  13. Amantea MA, Forrest A, Northfelt DW et al (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 61:301–311

    Article  CAS  PubMed  Google Scholar 

  14. Gabizon A, Catane R, Uziely B et al (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987–992

    CAS  PubMed  Google Scholar 

  15. Symon Z, Peyser A, Tzemach D et al (1999) Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes. Cancer 86:72–78

    Article  CAS  PubMed  Google Scholar 

  16. Sparano JA, Winer EP (2001) Liposomal anthracyclines for breast cancer. Semin Oncol 28:32–40

    CAS  PubMed  Google Scholar 

  17. O’Brien ME, Wigler N, Inbar M et al (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15:440–449

    Article  PubMed  Google Scholar 

  18. Keller AM, Mennel RG, Georgoulias VA et al (2004) Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22:3893–3901

    Article  CAS  PubMed  Google Scholar 

  19. Sparano JA, Malik U, Rajdev L et al (2001) Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer. J Clin Oncol 19:3117–3125

    CAS  PubMed  Google Scholar 

  20. Cortes J, DiCosimo S, Climent MA et al (2009) Nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2-overexpressing breast cancer: a multicenter phase I/II study. Clin Cancer Res 15:307–314

    Article  CAS  PubMed  Google Scholar 

  21. Andreopoulou E, Gaiotti D, Kim E et al (2007) Feasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancer. Clin Breast Cancer 7:690–696

    Article  CAS  PubMed  Google Scholar 

  22. Chia S, Clemons M, Martin LA et al (2006) Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial. J Clin Oncol 24:2773–2778

    Article  CAS  PubMed  Google Scholar 

  23. Stickeler E, Klar M, Watermann D et al (2009) Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial. Breast Cancer Res Treat 117(3):591–598

    Article  CAS  PubMed  Google Scholar 

  24. Wolff AC, Hammond ME, Schwartz JN et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145

    Article  CAS  PubMed  Google Scholar 

  25. Nagore E, Insa A, Sanmartin O (2000) Antineoplastic therapy-induced palmar plantar erythrodysesthesia (‘hand-foot’) syndrome. Incidence, recognition and management. Am J Clin Dermatol 1:225–234

    Article  CAS  PubMed  Google Scholar 

  26. Vail DM, Chun R, Thamm DH et al (1998) Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model. Clin Cancer Res 4:1567–1571

    CAS  PubMed  Google Scholar 

  27. Sparano JA, Hu P, Rao RM et al (1999) Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 17:3828–3834

    CAS  PubMed  Google Scholar 

  28. Sparano JA, O’Neill A, Schaefer PL et al (2000) Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E1196. J Clin Oncol 18:2369–2377

    CAS  PubMed  Google Scholar 

  29. Chan S, Friedrichs K, Noel D et al (1999) Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:2341–2354

    CAS  PubMed  Google Scholar 

  30. Sparano JA, Makhson AN, Semiglazov VF et al (2009) Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 27:4522–4529

    Article  PubMed  Google Scholar 

  31. Robert N, Leyland-Jones B, Asmar L et al (2006) Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24:2786–2792

    Article  CAS  PubMed  Google Scholar 

  32. Pegram M, Forbes J, Pienkowski T et al (2007) BCIRG 007: first overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). J Clin Oncol 25(18S) (Abstract 1008)

  33. Carrick S, Parker S, Wilcken N et al (2005) Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev CD003372

  34. Seidman AD (2003) Sequential single-agent chemotherapy for metastatic breast cancer: therapeutic nihilism or realism? J Clin Oncol 21:577–579

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the support from Ortho Biotech Products, L.P., for the provision of investigational drug and financial support for central HER2 testing and from Genentech, Inc., for the provision of investigational drugs. We are also grateful to Dako A/S and Abbott Molecular for their support with free assay kits for central HER2 testing, and to Adekunle Raji, Susan Edgerton, and other members of the ECOG Pathology Coordinating Office. This work was supported in part by grants from the Department of Health and Human Services and the National Institutes of Health CA23318 to the ECOG statistical center, CA66636 to the ECOG data management center, CA21115 to the ECOG coordinating center and chairman’s office, CA16116 to The Johns Hopkins Kimmel Cancer Center, CA59307 to the University of Pretoria, CA13650 to the Mayo Clinic (Carle Clinic), and CA14958 to the Albert Einstein College of Medicine.

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Author notes

  1. Michael R. Pins

    Present address: Advocate Lutheran General Hospital, Chicago, IL, USA

  2. Nancy E. Davidson

    Present address: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-189, Baltimore, MD, 21231-1000, USA

    Antonio C. Wolff & Nancy E. Davidson

  2. Dana Farber Cancer Institute, Boston, MA, USA

    Molin Wang & Hailun Li

  3. Northwestern University, Chicago, IL, USA

    Michael R. Pins

  4. University of Pretoria, Pretoria, South Africa

    Florence J. Pretorius

  5. Carle Clinic, Urbana, IL, USA

    Kendrith M. Rowland

  6. Montefiore-Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Joseph A. Sparano

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  1. Antonio C. Wolff
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  2. Molin Wang
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Corresponding author

Correspondence to Antonio C. Wolff.

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The study was conducted on behalf of the Eastern Cooperative Oncology Group.

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Wolff, A.C., Wang, M., Li, H. et al. Phase II trial of pegylated liposomal doxorubicin plus docetaxel with and without trastuzumab in metastatic breast cancer: Eastern Cooperative Oncology Group Trial E3198. Breast Cancer Res Treat 121, 111–120 (2010). https://doi.org/10.1007/s10549-010-0838-7

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  • DOI: https://doi.org/10.1007/s10549-010-0838-7

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